Simon Koplev, Osheen Sharma, Simon Woelfel, Ni Huang, Mathilde Pohin, Adrian Feile, Maria Warschinke, Mikel Rezola Artero, Sharujan Suthakaran, Ioannis Sarropoulos, J Patrick Pett, Julia Nyman, Tom Thomas, Duy Pham, Bin Li, Moustafa Attar, Julia Pakpoor, Kate Milosevic-Hutton, Alistair Easton, Matt Butler, James Dunford, Martin Philpott, Mark Coles, Christopher D Buckley, Calliope Dendrou, Khalid Shamiyah, Lorenz Kretschmer, Lisa Dratva, Fadi Issa, Joanna Hester, Jens Rittscher, Alissa Walsh, Simon P Travis, Fränze Progatzky, Lukas W Unger, Mark Bignell, Katherine Baker, Bruce George, Hussein Al-Mossawi, Paul Klenerman, Alexander S Mosig, Udo Oppermann, Sarah A Teichmann, Fiona M Powrie, Matthias Friedrich
Stromal cell states are altered in active Crohn's disease (CD), but their origin and phenotypic stability are unknown. Using single-cell spatial transcriptomics, RNA sequencing and ATAC sequencing of ~2,500,000 cells, we map 18 distinct stromal cell states within their cellular and cytokine signaling environments in human full-thickness CD bowel. Inflammatory fibroblasts (IFs) reside in immune cell-rich mucosal ulcers and are induced through combinatorial cytokine exposure suppressing submucosal universal fibroblast programs. The IF state is stabilized through transcription factor (TF) activity of GLI3, TWIST1, ETV4, PRDM1 and RELB, and does not spontaneously revert; however, histone deacetylase inhibition destabilizes the IF state, preventing IF secretome-induced epithelial transmigration and activation of neutrophils. The IF open chromatin configuration is distinct from that of fibrotic contractile stroma, which populate adjoining immune-depleted submucosal fibrotic niches. These findings show that microenvironments in pathological tissue niches shape open chromatin configuration of stromal states that are amenable to modulation by epigenetic modifiers.